Studying Pathogenic Mechanism of Hereditary Cerebral Amyloid Angiopathy

遗传性脑淀粉样血管病发病机制研究

• 批准号: 10320430
• 负责人: Hyung Jin Ahn
• 金额: $ 39.75万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320430
• 关键词: Abeta synthesis; Affect; Affinity; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Autopsy; Binding; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood coagulation; Brain; Cerebral Amyloid Angiopathy; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cessation of life; Clinical; Coagulation Process; Dementia; Deposition; Diagnosis; Disease; Familial Cerebral Amyloid Angiopathy; Fibrin; Fibrin split products; Fibrinogen; Fibrinolysis; Functional disorder; Gene Proteins; Genes; Human; In Vitro; Incidence; Individual; Inflammation; Iowa; Late Onset Alzheimer Disease; Lead; Methods; Molecular; Mutation; N-terminal; Neurologic Dysfunctions; Pathogenicity; Pathologic; Pathology; Patients; Peptides; Play; Reporting; Research; Risk; Risk Factors; Role; Sampling; Scheme; Spectrum Analysis; Stroke; Structure; Therapeutic; Thrombosis; Vascular Diseases; abeta deposition; base; brain tissue; cerebrovascular; cerebrovascular pathology; early onset; experimental study; in vivo; in vivo imaging; inhibitor; mouse model; mutant; non-demented; novel; vascular contributions

Many Alzheimer's disease (AD) patients suffer from altered cerebral blood flow and a damaged cerebral vasculature. Moreover, the majority of patients with dementia present with both AD and vascular pathologies. Circulatory deficiencies could therefore play an important role in this disease. Cerebral amyloid angiopathy (CAA), where Aβ deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in AD and is observed in more than 80% of AD patients. Post-mortem pathological examination of patients' brains with CAA shows perivascular microhemorrhage, microinfarcts, and capillary occlusion. However, the molecular mechanism underlying CAA formation and CAA-induced cerebrovascular pathology is unclear. In addition, a definitive diagnosis of CAA requires autopsy as there is no clear biomarker for CAA. There are rare familiar forms of CAA, called hereditary cerebral amyloid angiopathy (HCAA), in which patients display exaggerated CAA pathology and a severe clinical course of strokes as well as suffering from early onset neurological dysfunction, dementia, and ultimately death. The majority of HCAA occurrences coincide with mutations within the gene for the β-amyloid precursor protein (APP). While most APP mutations elevate total Aβ production or promote formation of the more toxic Aβ42, a subset of mutations related to HCAA causes an increase in vascular deposits of Aβ. Since patients afflicted by HCAA mutations have severe cerebrovascular deficits along with massive CAA, HCAA is an ideal disease to examine the pathogenic mechanisms of CAA. Increasing evidence suggests that fibrinogen, a major component of blood clots, contributes heavily to the cerebrovascular risk in AD. Fibrinogen binds to Aβ with high affinity, and this interaction increases the incidence of abnormal fibrin clots, CAA, inflammation, and cerebrovascular damage. Our preliminary results indicate that HCAA mutations highly increase Aβ’s binding affinity for fibrinogen and induce more severely altered fibrin clot structure than wild-type (WT) Aβ. Based on these findings, we hypothesize that HCAA mutations increase Aβ’s binding affinity for fibrinogen, which subsequently induces more severely altered fibrin clotting, increases vascular fibrin and Aβ deposition, and exacerbates inflammation and cerebrovascular damage. By investigating our hypothesis in a mouse model of HCAA, as well as antemortem CSF and postmortem brain tissue of HCAA patients, we aim to understand the molecular mechanism underlying increased CAA and cerebrovascular abnormalities in HCAA. If our proposed experiments are successful, the results will help us to better understand the pathogenic mechanism underlying the vascular contribution of CAA in both AD and HCAA patients. In addition, our research will provide a novel CSF biomarker for CAA. Furthermore, these findings may accelerate the discovery of tractable therapeutic methods for vascular pathology in AD.

许多阿尔茨海默病(AD)患者大脑血流改变，大脑受损 脉管系统。此外，大多数痴呆症患者同时存在AD和血管病理。 因此，循环缺陷可能在这种疾病中发挥重要作用。脑淀粉样血管病 Aβ沉积在脑血管周围，是AD患者血管功能障碍的主要原因 并且在80%以上的AD患者中观察到。病人脑部的死后病理检查 CAA显示血管周围微出血、微梗塞和毛细血管闭塞。然而，分子 CAA形成的机制和CAA引起的脑血管病变机制尚不清楚。此外，a CAA的明确诊断需要尸检，因为CAA没有明确的生物标志物。 有一种罕见的常见形式的CAA，称为遗传性脑淀粉样血管病(HCAA)，患者 显示夸张的CAA病理和严重的中风和早期中风的临床病程 出现神经功能障碍，痴呆症，最终死亡。大多数HCAA的发生与 与β-淀粉样前体蛋白(APP)基因突变有关。虽然大多数应用程序的突变都会提升 全Aβ的产生或促进形成毒性更大的Aβ42，这是与HCAA相关的突变的子集 导致Aβ的血管沉积增加。由于受HCAA突变困扰的患者有严重的 脑血管缺陷伴大量CAA，HCAA是检查病原学的理想疾病 CAA的作用机制。 越来越多的证据表明，纤维蛋白原是血栓的主要成分，对 阿尔茨海默病的脑血管风险。纤维蛋白原以高亲和力与Aβ结合，这种相互作用增加了 异常纤维蛋白凝块、CAA、炎症和脑血管损伤的发生率。我们的初步结果 提示HcaA突变显著增加了Aβ‘S与纤维蛋白原的结合亲和力，并导致更严重的诱导 与野生型(WT)Aβ相比，纤维蛋白凝块结构发生改变。基于这些发现，我们假设HCAA 突变增加Aβ‘S与纤维蛋白原的结合亲和力，从而导致更严重的纤维蛋白变化 凝血，增加血管纤维蛋白和Aβ沉积，并加剧炎症和脑血管 损坏。通过在HCAA小鼠模型以及生前和死后脑脊液中检验我们的假设 我们的目的是了解HCAA患者死后脑组织的分子机制 HCAA患者CAA和脑血管异常增加。如果我们提议的实验成功， 这些结果将有助于我们更好地了解CAA对血管的贡献的致病机制 在AD和HCAA患者中。此外，本研究还将为CAA提供一种新的脑脊液生物标志物。 此外，这些发现可能会加速发现易于处理的血管治疗方法。 AD中的病理学。